Hypertrophic cardiomyopathy 6

Summary

Hypertrophic cardiomyopathy 6 (MONDO:0010946) is a disease caused by PRKAG2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PRKAG2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 133

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertrophic cardiomyopathy 6
Mondo ID	MONDO:0010946
MeSH	C563436
OMIM	600858
DOID	DOID:0110312
UMLS	C1833236
MedGen	331466
GARD	0024763
Is cancer (heuristic)	no

Also known as: cardiomyopathy, familial hypertrophic, 6 · cardiomyopathy, familial hypertrophic, type 6 · cardiomyopathy, hypertrophic 6 · CMH6 · hypertrophic cardiomyopathy 6 · hypertrophic cardiomyopathy caused by mutation in PRKAG2 · hypertrophic cardiomyopathy type 6 · PRKAG2 hypertrophic cardiomyopathy

Data availability: 133 ClinVar variants · 2 GenCC gene-disease records · 8 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › hypertrophic cardiomyopathy › familial hypertrophic cardiomyopathy › hypertrophic cardiomyopathy 6

Related subtypes (39): hypertrophic cardiomyopathy 2, hypertrophic cardiomyopathy 3, hypertrophic cardiomyopathy 4, Beckwith-Wiedemann syndrome, myotonic dystrophy type 1, hypertrophic cardiomyopathy 1, very long chain acyl-CoA dehydrogenase deficiency, multiple acyl-CoA dehydrogenase deficiency, 46,XY complete gonadal dysgenesis, dilated cardiomyopathy 1C, hypertrophic cardiomyopathy 25, hypertrophic cardiomyopathy 8, hypertrophic cardiomyopathy 10, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, cardiomyopathy-hypotonia-lactic acidosis syndrome, hypertrophic cardiomyopathy 11, hypertrophic cardiomyopathy 12, hypertrophic cardiomyopathy 13, hypertrophic cardiomyopathy 14, hypertrophic cardiomyopathy 15, hypertrophic cardiomyopathy 7, hypertrophic cardiomyopathy 9, hypertrophic cardiomyopathy 16, hypertrophic cardiomyopathy 17, hypertrophic cardiomyopathy 18, hypertrophic cardiomyopathy 19, hypertrophic cardiomyopathy 20, hypertrophic cardiomyopathy 21, dilated cardiomyopathy 1KK, hypertrophic cardiomyopathy 26, Noonan syndrome and Noonan-related syndrome, long chain acyl-CoA dehydrogenase deficiency, cardiomyopathy, familial hypertrophic, 28, cardiomyopathy, familial hypertrophic 27, cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction, cardiomyopathy, familial restrictive, 5, cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, cardiomyopathy, familial hypertrophic, 30, atrial, cardiomyopathy, familial hypertrophic, 31

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

133 retrieved; paginated sample, class counts are floors:

64 uncertain significance, 40 conflicting classifications of pathogenicity, 10 benign/likely benign, 8 benign, 4 likely benign, 4 pathogenic, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
6846	NM_016203.4(PRKAG2):c.905G>A (p.Arg302Gln)	PRKAG2	Pathogenic	criteria provided, multiple submitters, no conflicts
6848	NM_016203.4(PRKAG2):c.1050_1051insTTA (p.Arg350_Glu351insLeu)	PRKAG2	Pathogenic	no assertion criteria provided
6850	NM_016203.4(PRKAG2):c.1463A>T (p.Asn488Ile)	PRKAG2	Pathogenic	no assertion criteria provided
6854	NM_016203.4(PRKAG2):c.1589A>G (p.His530Arg)	PRKAG2	Pathogenic	criteria provided, multiple submitters, no conflicts
3544408	NM_016203.4(PRKAG2):c.466+45171G>T	PRKAG2	Likely pathogenic	criteria provided, single submitter
6849	NM_016203.4(PRKAG2):c.1199C>A (p.Thr400Asn)	PRKAG2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
6855	NM_016203.4(PRKAG2):c.1516G>C (p.Glu506Gln)	PRKAG2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
378428	NM_016203.4(PRKAG2):c.750C>T (p.Asp250=)	LOC129999660	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
410720	NM_016203.4(PRKAG2):c.704T>G (p.Leu235Arg)	LOC129999660	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
45733	NM_016203.4(PRKAG2):c.698C>G (p.Ala233Gly)	LOC129999660	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
177987	NM_016203.4(PRKAG2):c.*2C>T	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
181469	NM_016203.4(PRKAG2):c.556C>T (p.Arg186Trp)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
181473	NM_016203.4(PRKAG2):c.866T>C (p.Val289Ala)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
227880	NM_016203.4(PRKAG2):c.981A>G (p.Leu327=)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359332	NM_016203.4(PRKAG2):c.*614A>T	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359338	NM_016203.4(PRKAG2):c.*365G>A	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359340	NM_016203.4(PRKAG2):c.*135T>C	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359341	NM_016203.4(PRKAG2):c.*127C>G	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359343	NM_016203.4(PRKAG2):c.*55C>T	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359345	NM_016203.4(PRKAG2):c.433G>A (p.Gly145Arg)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359346	NM_016203.4(PRKAG2):c.429G>A (p.Ser143=)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359348	NM_016203.4(PRKAG2):c.248C>T (p.Pro83Leu)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359349	NM_016203.4(PRKAG2):c.224G>C (p.Gly75Ala)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359351	NM_016203.4(PRKAG2):c.138G>A (p.Pro46=)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
359352	NM_016203.4(PRKAG2):c.-16A>G	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3594434	NM_016203.4(PRKAG2):c.904C>G (p.Arg302Gly)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
36697	NM_016203.4(PRKAG2):c.298G>A (p.Gly100Ser)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
389634	NM_016203.4(PRKAG2):c.1679-3C>T	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
45686	NM_016203.4(PRKAG2):c.1098A>G (p.Pro366=)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
45687	NM_016203.4(PRKAG2):c.1106+9G>C	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PRKAG2	Definitive	Autosomal dominant	hypertrophic cardiomyopathy 6	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRKAG2	Orphanet:439854	Fatal congenital hypertrophic cardiomyopathy due to glycogen storage disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRKAG2	HGNC:9386	ENSG00000106617	Q9UGJ0	5’-AMP-activated protein kinase subunit gamma-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRKAG2	5’-AMP-activated protein kinase subunit gamma-2	AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRKAG2	Other/Unknown	no		CBS_dom, CBS_dom_sf, AMPK_gamma/SDS23_families

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac atrium	1
cardiac muscle of right atrium	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRKAG2	258	ubiquitous	marker	right atrium auricular region, cardiac atrium, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKAG2	3,212

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRKAG2	Q9UGJ0	67.24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 33. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
AMPK inhibits chREBP transcriptional activation activity	1	1427.5×	0.010	PRKAG2
Lipophagy	1	1268.9×	0.010	PRKAG2
Activation of PPARGC1A (PGC-1alpha) by phosphorylation	1	1142.0×	0.010	PRKAG2
Carnitine shuttle	1	761.3×	0.011	PRKAG2
Energy dependent regulation of mTOR by LKB1-AMPK	1	393.8×	0.014	PRKAG2
Activation of AMPK downstream of NMDARs	1	380.7×	0.014	PRKAG2
Selective autophagy	1	278.5×	0.014	PRKAG2
MTOR signalling	1	265.6×	0.014	PRKAG2
Post NMDA receptor activation events	1	203.9×	0.014	PRKAG2
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	1	193.6×	0.014	PRKAG2
Activation of NMDA receptors and postsynaptic events	1	184.2×	0.014	PRKAG2
Integration of energy metabolism	1	175.7×	0.014	PRKAG2
Mitochondrial biogenesis	1	167.9×	0.014	PRKAG2
Translocation of SLC2A4 (GLUT4) to the plasma membrane	1	154.3×	0.014	PRKAG2
Autophagy	1	148.3×	0.014	PRKAG2
Regulation of TP53 Activity	1	132.8×	0.014	PRKAG2
Fatty acid metabolism	1	131.3×	0.014	PRKAG2
TP53 Regulates Metabolic Genes	1	129.8×	0.014	PRKAG2
Regulation of TP53 Activity through Phosphorylation	1	117.7×	0.014	PRKAG2
Macroautophagy	1	115.3×	0.014	PRKAG2
Neurotransmitter receptors and postsynaptic signal transmission	1	100.2×	0.016	PRKAG2
Transmission across Chemical Synapses	1	76.1×	0.020	PRKAG2
Organelle biogenesis and maintenance	1	66.0×	0.022	PRKAG2
Transcriptional Regulation by TP53	1	62.1×	0.022	PRKAG2
Neuronal System	1	44.3×	0.030	PRKAG2
Membrane Trafficking	1	37.1×	0.034	PRKAG2
Vesicle-mediated transport	1	34.8×	0.035	PRKAG2
Metabolism of lipids	1	31.6×	0.037	PRKAG2
RNA Polymerase II Transcription	1	22.5×	0.051	PRKAG2
Gene expression (Transcription)	1	17.8×	0.062	PRKAG2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of carbon utilization	1	5617.3×	0.001	PRKAG2
regulation of fatty acid oxidation	1	5617.3×	0.001	PRKAG2
regulation of D-glucose import across plasma membrane	1	2106.5×	0.002	PRKAG2
regulation of fatty acid metabolic process	1	1872.4×	0.002	PRKAG2
sterol biosynthetic process	1	1685.2×	0.002	PRKAG2
regulation of glycolytic process	1	1203.7×	0.002	PRKAG2
ATP biosynthetic process	1	991.3×	0.002	PRKAG2
positive regulation of gluconeogenesis	1	766.0×	0.002	PRKAG2
glycogen metabolic process	1	526.6×	0.003	PRKAG2
cellular response to nutrient levels	1	468.1×	0.003	PRKAG2
fatty acid biosynthetic process	1	351.1×	0.003	PRKAG2
cellular response to glucose starvation	1	337.0×	0.003	PRKAG2
regulation of cell cycle	1	74.6×	0.014	PRKAG2
intracellular signal transduction	1	38.1×	0.026	PRKAG2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PRKAG2	ADENOSINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKAG2	19	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADENOSINE PHOSPHATE	4	PRKAG2
CAPIVASERTIB	4	PRKAG2
SUNITINIB	4	PRKAG2
MIDOSTAURIN	4	PRKAG2
CRENOLANIB	3	PRKAG2
DOVITINIB	3	PRKAG2
LESTAURTINIB	3	PRKAG2
SILMITASERTIB	2	PRKAG2
REFAMETINIB	2	PRKAG2
DANUSERTIB	2	PRKAG2
AT-9283	2	PRKAG2
UCN-01	2	PRKAG2
BMS-754807	2	PRKAG2
SGI-1776	1	PRKAG2
AZD-7762	1	PRKAG2
PF-03758309	1	PRKAG2
TAK-901	1	PRKAG2
PF-03814735	1	PRKAG2
GSK-690693	1	PRKAG2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PRKAG2	266	Binding:265, Functional:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PRKAG2	266

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

19 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ADENOSINE PHOSPHATE	4	PRKAG2
CAPIVASERTIB	4	PRKAG2
SUNITINIB	4	PRKAG2
MIDOSTAURIN	4	PRKAG2
CRENOLANIB	3	PRKAG2
DOVITINIB	3	PRKAG2
LESTAURTINIB	3	PRKAG2
SILMITASERTIB	2	PRKAG2
REFAMETINIB	2	PRKAG2
DANUSERTIB	2	PRKAG2
AT-9283	2	PRKAG2
UCN-01	2	PRKAG2
BMS-754807	2	PRKAG2
SGI-1776	1	PRKAG2
AZD-7762	1	PRKAG2
PF-03758309	1	PRKAG2
TAK-901	1	PRKAG2
PF-03814735	1	PRKAG2
GSK-690693	1	PRKAG2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PRKAG2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.